The effects of NN414, a SUR1/Kir6.2 selective potassium channel opener in subjects with type 2 diabetes.

Reducing the workload of the beta cell by inhibiting insulin secretion may provide beneficial effects for patients with type 2 diabetes. The aim of this study was to investigate the effect of NN414, a beta cell selective potassium channel opener in patients with type 2 diabetes. 24 patients were treated for seven days (placebo, 1.5, 4.5, and 10 mg/kg). In accordance with the pharmacological profile a significant and selective inhibition of insulin secretion was observed (1 h post dose). There were no statistically significant effects on overall glycaemic control. Based on OGTT derived parameters a borderline significant improvement in beta-cell function (1st and 2nd phase insulin secretion) was observed from Day 1 to Day 7.

In vivo detection of tobacco mosaic virus-induced local and systemic oxidative burst by electron paramagnetic resonance spectroscopy.

This is the first demonstration that tobacco mosaic virus-induced oxidative stress in a necrotic host plant is signalled by an elevated level of monodehydroascorbate (MDA) radicals detected by electron paramagnetic resonance spectroscopy. Furthermore, systemic acquired resistance induced in remote leaves of Xanthi-nc tobacco is also associated with stimulated MDA signals indicative of a microoxidative burst.

Percutaneous absorption of methylprednisolone aceponate following topical application of Advantan lotion on intact, inflamed and stripped skin of male volunteers.

Six healthy, elderly volunteers received three topical treatments with Advantan lotion containing 0.1% of methylprednisolone aceponate (MPA, CAS 86401-95-8) on intact, inflamed and stripped skin in a consecutive fashion at weekly intervals. The lotion (O/W emulsion) containing 14C-MPA (specific radioactivity 1.8 MBq/mg MPA) was applied in an area dose of 5 mg lotion/cm2 on a marked area of 100 cm2 on the back for 24 h. Inflammation was caused by UV-B irradiation at 3 MED 6 h prior to the treatment with the test preparation. Removal of stratum corneum was performed by 20-fold adhesive tape stripping. The concentration of radioactivity was measured in the plasma and in the urine up to 7 days following each treatment. The concentration of radioactivity in the plasma did not exceed the limit of detection of 1.5 ng MPA Eq/ml at any time point. The percutaneous absorption was assessed from the cumulated excretion of radiolabelled substances in the urine corrected for biliary excretion. Less than 0.5% of the dose was percutaneously absorbed through intact skin and through inflamed skin. After removal of the penetration barrier ('stripping') the percutaneous absorption increased to 15.4 +/- 7.7% of the applied dose.

Arachidonic acid metabolism in primary irritant dermatitis produced by patch testing of human skin with surfactants.

A clinical study was performed to determine the effects of patch testing human skin with four industrially used surfactants on erythema formation, transepidermal water loss, and the contents in suction blister fluids of primary proinflammatory mediators including arachidonic acid, eicosanoids, and IL-1 alpha, which were analyzed by quantitative gas chromatography/negative ion chemical ionization mass spectrometry and by an enzyme-immunoassay, respectively. Benzalkonium chloride (BKCI) and sodium lauryl sulfate (SLS) elicited erythema and caused increased transepidermal water loss, indicating a disturbance of the epidermal barrier. Triethanolamine (TEA) and Tween 80 did not evoke these gross symptoms of inflammation. Suction blister fluids collected after a 24-h application of BKCl, SLS, and Tween 80 contained significantly increased amounts of individual eicosanoids whereas TEA induced no response. The induced eicosanoid profile was characteristic for each compound, pointing to different cell types of skin to be involved in their production. The elevation of prostaglandin and LTB4 contents correlated with the induction of erythema and the impairment of the epidermal barrier as shown for BKCl and SLS and preceded the maximum of erythema formation. IL-1 alpha contents did not correlate with these gross symptoms of inflammation. The results of this in vivo study support those of a previous study using human keratinocytes in culture indicating the release of arachidonic acid and prostaglandins to be an early event involved in the interaction of keratinocytes with surfactants. Moreover, the in vivo data with human skin underscore the mechanistic relationship to the in vitro model and support the concept that arachidonic acid and eicosanoid release from keratinocytes can be used as a marker of primary skin irritation.

Comparison of the local and systemic side effects of methylprednisolone aceponate and mometasone furoate applied as ointments with equal antiinflammatory activity.

BACKGROUND: The therapy for skin diseases with topical glucocorticoids is limited by their local and systemic side effects. A glucocorticoid with an improved benefit-to-risk ratio is desirable. OBJECTIVE: A new topical corticoid, methylprednisolone aceponate (MPA) 0.1% ointment, was compared with the same formulation of mometasone furoate. METHODS: The two ointments were compared with respect to suppression of UVB light-induced erythema (n = 20) and with respect to atrophogenicity and appearance of telangiectasia (n = 20) in two double-blind trials with intraindividual comparisons in healthy volunteers. In a third trial, serum cortisol levels were measured in volunteers receiving extensive (60% of body surface) cutaneous application of MPA (n = 10) or mometasone furoate (n = 11). RESULTS: MPA and mometasone furoate were equally effective in suppressing UVB light-induced erythema. Atrophogenicity, as well as the incidence and severity of telangiectasia, were significantly more pronounced with mometasone furoate than with MPA. Both ointments decreased serum cortisol levels and did not differ significantly in this respect. However, the incidence of serum cortisol level suppression was higher in the mometasone furoate group than in the MPA group. CONCLUSION: MPA ointment has equal antiinflammatory activity and similar cortisol suppression but significantly fewer local side effects than mometasone furoate.

Activity of topically applied methylprednisolone aceponate in relation to other topical glucocorticosteroids in healthy volunteers.

Topical glucocorticosteroids are useful in the treatment of various skin diseases. Although there are already many corticosteroids available, there is still need for highly potent and well tolerated ones. The anti-inflammatory activity of methylprednisolone aceponate (MPA, CAS 86401-95-8) has been investigated in 165 healthy volunteers of either sex. UV-B irradiation or cellophane tape stripping has served to produce erythema. First, the dose response relationship of MPA ointment (0.01%, 0.05%, 0.1% and 0.5%) has been evaluated. MPA effects have been related to those of the vehicle and difluocortolone 21-valerate 0.1% (DFV) ointment. Then the activity of 0.1% MPA (cream, ointment and fatty ointment) has been related to those of the respective vehicles as well as commercially available preparations of five corticosteroids: betamethasone 17,21-dipropionate 0.64% (BDP), betamethasone 17-valerate 0.1% (BV), clobetasol 17-propionate 0.05% (CP), hydrocortisone 17-butyrate 0.1% (HCB), prednicarbate 0.25% (P). In each experiment, MPA activity significantly exceeded that of the respective vehicle (p < or = 0.05). MPA 0.01-0.5% ointment exhibited strong anti-inflammatory activity, at least corresponding to that of 0.1% DFV ointment. A dose-dependent activity could only be observed in the UV-B-erythema test using 3 fold MED (minimal erythema doses) for irradiation, a test model differentiating strong corticosteroids. The comparison of 0.1% MPA formulations with respective reference preparations showed the following results: On stripped skin no significant differences could be detected which is demonstrated in the example of cream formulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-response relationship of topically applied methylprednisolone aceponate (MPA) in healthy volunteers.

Topical glucocorticosteroids are useful in the treatment of various skin diseases. Although many corticosteroids are available today, there is still a need for highly potent compounds with minimal adverse effects. Methylprednisolone aceponate (MPA) has recently been synthesized. Its activity has been evaluated using the vasoconstrictor assay and the poison ivy test (rhus dermatitis) in 19/20 healthy volunteers of either sex. Comparable blanching was found with MPA in a cream vehicle, in an ointment and a fatty ointment. Vasoconstriction and suppression of experimentally-induced poison ivy contact dermatitis were dose-dependent in the concentration range 0.01% to 0.5% MPA. Concentrations of MPA of at least 0.05% were significantly active. Following the highest dose, blanching was close to the maximum which can be obtained. This finding, and the improvement of rhus dermatitis, suggest that MPA belongs to the highly potent local glucocorticosteroids.

[Assessment of the antiphlogistic effect of naftifin-HCl in the UV-B erythema test]. / Nachweis der antiphlogistischen Wirkung von Naftifin-HCl im UV-B-Erythemtest.

In a placebo-controlled double-blind comparative study conducted in 19 healthy volunteers, naftifin hydrochlorid cream was tested against clotrimazole 1%, clotrimazole 1%+hydrocortisone 1%, and various hydrocortisone preparations (0.5%; 1%; 2.5%) for erythema-suppressive effects. The anti-inflammatory effect of naftifine hydrochloride demonstrated earlier was confirmed in this study. The results prove a potency comparable to that of weak topical glucocorticosteroids.